TY - JOUR TI - SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration AU - Sasaki, Yo AU - Kakita, Hiroki AU - Kubota, Shunsuke AU - Sene, Abdoulaye AU - Lee, Tae Jun AU - Ban, Norimitsu AU - Dong, Zhenyu AU - Lin, Joseph B AU - Boye, Sanford L AU - DiAntonio, Aaron AU - Boye, Shannon E AU - Apte, Rajendra S AU - Milbrandt, Jeffrey A2 - Mason, Carol A A2 - Zoghbi, Huda Y VL - 9 PY - 2020 DA - 2020/10/27 SP - e62027 C1 - eLife 2020;9:e62027 DO - 10.7554/eLife.62027 UR - https://doi.org/10.7554/eLife.62027 AB - Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies. KW - retinal degenerations KW - NAD+ KW - SARM1 KW - NMNAT1 KW - LCA9 KW - axonal degeneration JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -